The present invention relates to novel classes of compounds which are inhibitors of interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d). The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against interleukin-1 (xe2x80x9cIL-1xe2x80x9d) mediated diseases, including inflammatory diseases, autoimmune diseases and neurodegenerative diseases. This invention also relates to methods for inhibiting ICE activity and methods for treating interleukin-1 mediated diseases using the compounds and compositions of this invention.
Interleukin 1 (xe2x80x9cIL-1xe2x80x9d) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J. H. et al, Immunology Today, 7, pp. 45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response and exists in two distinct agonist forms, IL-1xcex1 and IL-1xcex2. Mosely, B. S. et al., Proc. Nat. Acad. Sci., 84, pp. 4572-4576 (1987); Lonnemann, G. et al., Eur. J. Immunol., 19, pp. 1531-1536 (1989).
IL-1xcex2 is synthesized as a biologically inactive precursor, pIL-1xcex2. pIL-1xcex2 lacks a conventional leader sequence and is not processed by a signal peptidase. March, C. J., Nature, 315, pp. 641-647 (1985). Instead, pIL-1xcex2 is cleaved by interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P. R., et al., J. Biol. Chem., 265, pp. 14526-14528 (1992); A. D. Howard et al., J. Immunol., 147, pp. 2964-2969 (1991). Processing by ICE is also necessary for the transport of mature IL-1xcex2 through the cell membrane.
ICE is a cysteine protease localized primarily in monocytes. It converts precursor IL-1xcex2 to the mature form. Black, R. A. et al., FEBS Lett., 247, pp. 386-390 (1989); Kostura, M. J. et al., Proc. Natl. Acad. Sci. USA, 86, pp. 5227-5231 (1989). ICE, or its homologues, also appears to be involved in the regulation of cell death or apoptosis. Yuan, J. et al., Cell, 75, pp. 641-652 (1993); Miura, M. et al., Cell, 75, pp. 653-660 (1993); Nett-Fiordalisi, M. A. et al., J. Cell Biochem., 17B, p. 117 (1993). In particular, ICE or ICE homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer""s and Parkinson""s disease. Marx, J. and M. Baringa, Science, 259, pp. 760-762 (1993); Gagliardini, V. et al., Science, 263, pp. 826-828 (1994).
ICE has been previously described as a heterodimer composed of two subunits, p20 and p10 (20 kDa and 10 kDa molecular weight, respectively). These subunits are derived from a 45 kDa proenzyme (p45) by way of a p30 form, through an activation mechanism that is autocatalytic. Thornberry, N. A. et al., Nature, 356, pp. 768-774 (1992). The ICE proenzyme has been divided into several functional domains: a prodomain (p14), a p22/20 subunit, a polypeptide linker and a p10 subunit. Thornberry et al., supra; Casano et al., Genomics, 20, pp. 474-481 (1994).
Full length p45 has been characterized by its cDNA and amino acid sequences. PCT patent applications WO 91/15577 and WO 94/00154. The p20 and p10 cDNA and amino acid sequences are also known. Thornberry et al., supra. Murine and rat ICE have also been sequenced and cloned. They have high amino acid and nucleic acid sequence homology to human ICE. Miller, D. K. et al., Ann. N.Y. Acad. Sci., 696, pp. 133-148 (1993); Molineaux, S. M. et al., Proc. Nat. Acad. Sci., 90, pp. 1809-1813 (1993). Knowledge of the primary structure of ICE, however, does not allow prediction of its tertiary structure. Nor does it afford an understanding of the structural, conformational and chemical interactions of ICE and its substrate pIL-1xcex2 or other substrates or inhibitors.
ICE inhibitors represent a class of compounds useful for the control of inflammation or apoptosis or both. Peptide and peptidyl inhibitors of ICE have been described. PCT patent applications WO 91/15577; WO 93/05071; WO 93/09135; WO 93/14777 and WO 93/16710; and European patent application 0 547 699. However, due to their peptidic nature, such inhibitors are typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J. J. and D. W. Norbeck, in Drug Discovery Technologies, C. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. This has hampered their development into effective drugs.
Accordingly, the need exists for compounds that can effectively inhibit the action of ICE, for use as agents for preventing and treating chronic and acute forms of IL-1 mediated diseases, including various cancers, as well as inflammatory, autoimmune or neurodegenerative diseases.
The present invention provides novel classes of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of ICE. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antibiotics, immunomodulators or other anti-inflammatory agents, for the treatment or prophylaxis of diseases mediated by IL-1. According to a preferred embodiment, the compounds of this invention are capable of binding to the active site of ICE and inhibiting the activity of that enzyme.
It is a principal object of this invention to provide novel classes of inhibitors of ICE. These novel classes of ICE inhibitors are characterized by the following structural and physicochemical features:
a) a first and a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide xe2x80x94NHxe2x80x94 group of Arg-341, the carbonyl oxygen of Ser-339 and the amide xe2x80x94NHxe2x80x94 group of Ser-339;
b) a first and a second moderately hydrophobic moiety, said moieties each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the Pxe2x80x2 binding pocket; and
c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being capable of forming one or more hydrogen bonds or salt bridges with residues in the Pi binding pocket of ICE.
It is also an object of this invention to provide a method for identification, design or prediction of ICE inhibitors comprising the steps of:
a) selecting a candidate compound of defined chemical structure comprising at least two hydrogen bonding moieties, at least two moderately hydrophobic moieties and one electronegative moiety comprising one or more electronegative atoms attached either to the same atom or to adjacent atoms in the electronegative moiety;
b) determining a low-energy conformation for binding of said compound to the active site of ICE;
c) evaluating the capability of said compound in said conformation to form at least two hydrogen bonds with the non-carbon backbone atoms of Arg-341 and Ser-339 of ICE;
d) evaluating the capability of said compound in said conformation to associate with at least two of the binding pockets of ICE selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the Pxe2x80x2 binding pocket;
e) evaluating the capability of said compound in said conformation to interact with the P1 binding pocket of ICE; and
f) accepting or rejecting said candidate compound as an ICE inhibitor based on the determinations and evaluations carried out in the preceding steps.
It is a further object of this invention to provide novel classes of ICE inhibitors represented by formulas: 
The following terms are employed herein:
The term xe2x80x9cactive sitexe2x80x9d refers to any or all of the following sites in ICE: the substrate binding site, the site where an inhibitor binds and the site where the cleavage of substrate occurs. The active site is characterized by at least amino acid residues: 173, 176, 177, 178, 179, 180, 236, 237, 238, 239, 244, 248, 283, 284, 285, 290, 338, 339, 340, 341, 342, 343, 344, 345, 348, 352, 381, 383, using the sequence and numbering according to Thornberry et al., supra.
The terms xe2x80x9cP binding pocketxe2x80x9d, xe2x80x9cS subsitexe2x80x9d, xe2x80x9cS pocketxe2x80x9d, and the like, refer to binding subsites, or portions of the substrate binding site on the ICE molecule. The amino acid residues of the substrate are given designations according to their position relative to the scissile bond, i.e. the bond which is broken by the protease. The residues are designated P1, P2, etc., for those extending toward the N-terminus of the substrate and P1xe2x80x2, P2xe2x80x2, etc., for those extending toward the C-terminus of the substrate. The portions of an inhibitor which correspond to the P or Pxe2x80x2 residues of the substrate are also labeled P1, P1xe2x80x2, etc., by analogy with the substrate. The binding subsites of the ICE molecule which receive the residues labeled P1, P1xe2x80x2, etc., are designated S1, S1xe2x80x2, etc., or may alternately be designated xe2x80x9cthe P1 binding pocketxe2x80x9d, xe2x80x9cthe P1xe2x80x2 binding pocketxe2x80x9d, etc. [I. Schechter and A. Berger, xe2x80x9cOn the Size of the Active Site in Proteasesxe2x80x9d, Biochem. Biophys. Res. Commun., vol. 27, pp. 157-162 (1967).]
The terms xe2x80x9cP2 binding pocketxe2x80x9d or xe2x80x9cS2 subsitexe2x80x9d of the ICE active site are equivalent and are defined as the space surrounded by amino acid residues Pro-290, Val-338 or Trp-340.
The terms xe2x80x9cP3 binding pocketxe2x80x9d or xe2x80x9cS3 subsitexe2x80x9d of the ICE active site are equivalent and are defined as the space surrounded by amino acid residues Pro-177, Arg-178, Thr-180, Arg-341 or Pro-343.
The terms xe2x80x9cP4 binding pocketxe2x80x9d or xe2x80x9cS4 subsitexe2x80x9d of the ICE active site are equivalent and are defined as the space surrounded by amino acid residues His-342, Met-345, Val-348, Arg-352, Asp-381, Arg-383 or Trp-340.
The terms xe2x80x9cP1 binding pocketxe2x80x9d or xe2x80x9cS1 subsitexe2x80x9d of the ICE active site are equivalent and are defined as the space surrounded by amino acid residues Arg-179, His-237, Gln-283, or Arg-341.
The terms xe2x80x9cPxe2x80x2 binding pocketxe2x80x9d or xe2x80x9cSxe2x80x2 subsitexe2x80x9d of the ICE active site are equivalent and are defined as the space surrounded by amino acid residues Phe-173, Ile-176, His-237, Gly-238, Ile-239, Cys-244 or His-248.
The term xe2x80x9chydrophobicxe2x80x9d refers to a moiety which tends not to dissolve in water and is fat-soluble. Hydrophobic moieties include, but are not limited to, hydrocarbons, such as alkanes, alkenes, alkynes, cycloalkanes, cycloalkenes, cycloalkynes and aromatic compounds, such as aryls, certain saturated and unsaturated heterocycles and moieties that are substantially similar to the side chains of hydrophobic natural and unnatural a-amino acids, including valine, leucine, isoleucine, methionine, phenylanine, xcex1-amino isobutyric acid, alloisoleucine, tyrosine, and tryptophan.
The term xe2x80x9cmoderately hydrophobicxe2x80x9d refers to a hydrophobic moiety in which one or two carbon atoms have been replaced with more polar atoms, such as oxygen or nitrogen.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a stable mono- or polycyclic compound which may optionally contain one or two double bonds or may optionally contain one or more aromatic rings. Each heterocycle consists of carbon atoms and from one to four heteroatoms independently selected from a group including nitrogen, oxygen, and sulfur. As used herein, the terms xe2x80x9cnitrogen heteroatomsxe2x80x9d and xe2x80x9csulphur heteroatomsxe2x80x9d include any oxidized form of nitrogen or sulfur and the quaternized form of any basic nitrogen. Heterocycles defined above include, for example, pyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinonlinyl, purinyl, pyrimidyl, indolinyl, benzimidazolyl, imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, xcex2-carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazolyl, benzodioxolyl, benzothienyl, tetrahydrothiophenyl and sulfolanyl. Further heterocycles are described in A. R. Katritzky and C. W. Rees, eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, NY (1984).
The term xe2x80x9ccycloalkylxe2x80x9d refers to a mono- or polycyclic group which contains 3 to 15 carbons and may optionally contain one or two double bonds. Examples include cyclohexyl, adamantyl and norbornyl.
The term xe2x80x9carylxe2x80x9d refers to a mono- or polycyclic group which contains 6, 10, 12, or 14 carbons in which at least one ring is aromatic. Examples include phenyl, naphthyl and biphenyl.
The term xe2x80x9cheteroaromaticxe2x80x9d refers to a mono- or polycyclic group which contains 1 to 15 carbon atoms and from 1 to 4 heteroatoms, each of which is selected independently from a group including sulphur, nitrogen and oxygen, and which additionally contains from 1 to 3 five or six membered rings, at least one of which is aromatic.
The term xe2x80x9calpha-amino acidxe2x80x9d (xcex1-amino acid) refers to both the naturally occurring amino acids and other xe2x80x9cnon-proteinxe2x80x9d xcex1-amino acids commonly utilized by those in the peptide chemistry arts when preparing synthetic analogues of naturally occurring peptides, including D and L forms. The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, xcex3-carboxyglutamic acid, arginine, ornithine and lysine. Examples of xe2x80x9cnon-proteinxe2x80x9d alpha-amino acids include hydroxylysine, homoserine, homotyrosine, homo-phenylalanine, citrulline, kynurenine, 4-amino-phenylalanine, 3-(2-naphthyl)-alanine, 3-(1-naphthyl)-alanine, methionine sulfone, t-butyl-alanine, t-butylglycine, 4-hydroxyphenylglycine, aminoalanine, phenylglycine, vinylalanine, propargyl-glycine, 1,2,4-triazolo-3-alanine, 4,4,4-trifluoro-threonine, thyronine, 6-hydroxytryptophan, 5-hydro-xytryptophan, 3-hydroxykynurenine, 3-aminotyrosine, trifuoromethylalanine, 2-thienylalanine, (2-(4-pyridyl)ethyl)-cystein, 3,4-dimethoxy-phenylalanine, 3-(2-thiazolyl)-alanine, ibotenic acid, 1-amino-1-cyclopentane-carboxylic acid, 1-amino-1-cyclohexanecarboxylic acid, quisqualic acid, 3-trifuoromethylphenylalanine, 4-trifuoro-methylphenylalanine, cyclohexylalanine, cyclo-hexylglycine, thiohistidine, 3-methoxytyrosine, elastatinal, norleucine, norvaline, alloisoleucine, homoarginine, thioproline, dehydroproline, hydroxyproline, isonipectotic acid, homoproline, cyclohexylglycine, xcex1-amino-n-butyric acid, cyclohexylalanine, aminophenylbutyric acid, phenylalanines substituted at the ortho, meta, or para position of the phenyl moiety with one or two of the following: a (C1-C4) alkyl, a (C1-C4) alkoxy, halogen or nitro groups or substituted with a methylenedioxy group; xcex2-2- and 3-thienylalanine, xcex2-2- and 3-furanylalanine, xcex2-2-, 3- and 4-pyridylalanine, xcex2-(benzothienyl-2- and 3-yl)alanine, xcex2-(1- and 2-naphthyl)alanine, O-alkylated derivatives of serine, threonine or tyrosine, S-alkylated cysteine, S-alkylated homocysteine, O-sulfate, O-phosphate and O-carboxylate esters of tyrosine, 3-sulfo-tyrosine, 3-carboxy-tyrosine, 3-phospho-tyrosine, 4-methane sulfonic acid ester of tyrosine, 4-methane phosphonic acid ester of tyrosine, 3,5-diiodotyrosine, 3-nitro-tyrosine, xcex5-alkyl lysine, and delta-alkyl ornithine. Any of these a-amino acids may be substituted with a methyl group at the alpha position, a halogen at any aromatic residue on the xcex1-amino side chain, or an appropriate protective group at the O, N, or S atoms of the side chain residues. Appropriate protective groups are disclosed in xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d T. W. Greene and P. G. M. Wuts, J. Wiley and Sons, New York, N.Y., 1991.
The term xe2x80x9cxcex1-amino acid side chain residuexe2x80x9d refers to a chemical moiety which is attached to the xcex1-carbon of an alpha-amino acid.
The term xe2x80x9cbioisosteric replacement for xe2x80x94CO2Hxe2x80x9d refers to group which may substitute for a carboxylic acid group in bioactive molecules. Examples of such groups are disclosed in Christopher A. Lipinski, xe2x80x9cBioisosteres in Drug Designxe2x80x9d Annual Reports In Medical Chemistry, 21, pp. 286-88 (1986), and in C. W. Thornber, xe2x80x9cIsosterism and Molecular Modification in Drug Designxe2x80x9d Chemical Society Reviews, pp. 563-580 (1979).
The term xe2x80x9cassociationxe2x80x9d is used in reference to a condition of proximity between an inhibitor or portions thereof to an ICE molecule or portions thereof wherein the juxtaposition is energetically favored by electrostatic or van der Waals interactions.
The term xe2x80x9chydrogen bondxe2x80x9d refers to a favorable interaction that occurs whenever a suitable donor atom, X, bearing a proton, H, and a suitable acceptor atom, Y, have a separation of between 2.5 xc3x85 and 3.5 xc3x85 and where the angle X-H - - - Y is greater than 90 degrees. Suitable donor and acceptor atoms are well understood in medicinal chemistry (G. C. Pimentel and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, xe2x80x9cHydrogen Bond Geometry in Organic Crystalsxe2x80x9d, Accounts of Chemical Research, 17, pp. 320-326 (1984)).
The term xe2x80x9csalt bridgexe2x80x9d refers to the non-covalent attractive interaction between a positively charged moiety (P) and a negatively charged moiety (N) when the distance between the centers of mass of P and N is between 2 and 6 Angstroms. In calculating the center of mass, atoms which may contain a formal charge and atoms immediately adjacent to these are included. For example, a salt bridge may be formed between the positively charged guanidinium side chain of an arginine residue and the negative charged carboxylate side chain of a glutamate residue. Salt bridges are well understood in medicinal chemistry (L. Stryer, Biochemistry, Freeman, San Francisco, (1975); K. A. Dill, xe2x80x9cDominant Forces in Protein Foldingxe2x80x9d, Biochemistry, 29, No. 31, pp. 7133-7155, (1990)).
The term xe2x80x9ccenter of massxe2x80x9d refers to a point in three-dimensional space which represents a weighted average position of the masses that make up an object.
The terms xe2x80x9cbackbone chainxe2x80x9d and xe2x80x9cbackbonexe2x80x9d refer to the portion of a polypeptide which comprises the repeating unit xe2x80x94COxe2x80x94CHxe2x80x94NHxe2x80x94.
The term xe2x80x9cscaffoldxe2x80x9d refers to a structural building block which forms the basis of an ICE inhibitor according to this invention. Various moieties and functional groups are intended to be appended to the scaffold. The scaffolds of this invention are thus depicted having open valences. Various scaffolds of ICE inhibitors according to this invention include the portions: 
In those scaffolds, the NH and CO or SO2 moieties represent a first and a second hydrogen bonding moiety, said moieties each being capable of forming a hydrogen bond with a backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide xe2x80x94NHxe2x80x94 of Arg-341, the carbonyl oxygen of Ser-339 and the amide xe2x80x94NHxe2x80x94 of Ser-339.
The term xe2x80x9csubstitutexe2x80x9d refers to the replacement of a hydrogen atom in a compound with a substituent group. In the present invention, those hydrogen atoms which form a part of a hydrogen bonding moiety which is capable of forming a hydrogen bond with the carbonyl oxygen of Arg-341 of ICE or the carbonyl oxygen of Ser-339 of ICE are excluded from substitution. These excluded hydrogen atoms include those which comprise an xe2x80x94NHxe2x80x94 group which is alpha to a Z or a xe2x80x94COxe2x80x94 group and are depicted as xe2x80x94NHxe2x80x94 rather than an X group or some other designation in the following diagrams: (a) through (t), (v) through (y), and (I) through (VIID).
The term xe2x80x9cstraight chainxe2x80x9d refers to a contiguous unbranching string of covalently bound members, i.e. atoms, which form a portion of a ring. The straight chain and the ring of which it forms a part may be substituted, but these substituents are not a part of the straight chain.
The term xe2x80x9cKixe2x80x9d refers to a numerical measure of the effectiveness of a compound in inhibiting the activity of a target enzyme such as ICE. Lower values of Ki reflect higher effectiveness. The Ki value is a derived by fitting experimentally determined rate data to standard enzyme kinetic equations (see I. H. Segel, Enzyme Kinetics, Wiley-Interscience, 1975).
The term xe2x80x9cminimizexe2x80x9d refers to the systematic altering of the atomic geometry of a molecule or molecular complex so that any further minor perturbation of the atomic geometry would cause the total energy of the system as measured by a molecular mechanics force-field to increase. Minimization and molecular mechanics force-fields are well understood in computational chemistry [U. Burkert and N. L. Allinger, Molecular Mechanics, ACS Monograph 177, American Chemical Society, Washington, D.C. 1982 pages 59-78].
The term xe2x80x9cstrain energyxe2x80x9d is used in this application to refer to the difference between the free conformation energy of a compound and the bound conformation energy of that compound when bound to ICE. The strain energy can be determined by the following steps: Evaluate the energy of the molecule when it has the conformation necessary for binding to ICE. Then minimize and reevaluate the energyxe2x80x94this is the free conformation energy. The strain energy for binding of a potential inhibitor to ICE is the difference between the free conformation energy and the bound conformation energy. In a preferred embodiment, the strain energy of an inhibitor of the present invention is less than about 10 kcal/mol.
The term xe2x80x9cpatientxe2x80x9d as used in this application refers to any mammal, especially humans.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d refers to an amount effective in treating or ameliorating an IL-1 mediated disease in a patient. The term xe2x80x9cprophylactically effective amountxe2x80x9d refers to an amount effective in preventing or substantially lessening IL-1 mediated disease in a patient.
The term xe2x80x9cpharmaceutically acceptable carrier or adjuvantxe2x80x9d refers to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
The term xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d means any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an anti-ICE active metabolite or residue thereof.
Pharmaceutically acceptable salts of the compounds of this invention include, for example, those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x80x94(C1-14 alkyl)4+ salts.
This invention also envisions the xe2x80x9cquaternizationxe2x80x9d of any basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The ICE inhibitors of this invention may contain one or more xe2x80x9casymmetricxe2x80x9d carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Although specific compounds and scaffolds exemplified in this application may be depicted in a particular stereochemical configuration, compounds and scaffolds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
The ICE inhibitors of this invention may comprise ring structures which may optionally be substituted at carbon, nitrogen or other atoms by various substituents. Such ring structures may be singly or multiply substituted. Preferably, the ring structures contain between 0 and 3 substituents. When multiply substituted, each substituent may be picked independently of any other substituent as long as the combination of substituents results in the formation of a stable compound.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term xe2x80x9cstablexe2x80x9d, as used herein, refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
In order that the invention herein described may be more fully understood, the following detailed description is set forth.
We have discovered that compounds possessing the following novel combination of features are surprisingly effective ICE inhibitors:
a) a first and a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide xe2x80x94NHxe2x80x94 group of Arg-341, the carbonyl oxygen of Ser-339 and the amide xe2x80x94NHxe2x80x94 group of Ser-339;
b) a first and a second moderately hydrophobic moiety, said moieties each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the Pxe2x80x2 binding pocket; and
c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of ICE.
Preferably, any moderately hydrophobic moiety associating with the P2 binding pocket of ICE does so in such a way that:
a) the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 7.1 xc3x85 and about 12.5 xc3x85;
b) the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 6.0 xc3x85 and about 12 xc3x85; and
c) the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 3.7 xc3x85 and about 9.5 xc3x85.
Preferably, any moderately hydrophobic moiety associating with the P3 binding pocket of ICE does so in such a way that:
a) the distance from the center of mass of the moderately hydrophobic moiety in the P3 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 3.9 xc3x85 and about 9.5 xc3x85;
b) the distance from the center of mass of the moderately hydrophobic moiety in the P3 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 5.4 xc3x85 and about 11 xc3x85; and
c) the distance from the center of mass of the moderately hydrophobic moiety in the P3 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 7.0 xc3x85 and about 13 xc3x85.
Preferably, any moderately hydrophobic moiety associating with the P4 binding pocket of ICE does so in such a way that:
a) the distance from the center of mass of the moderately hydrophobic moiety in the P4 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 4.5xc3x85 and about 7.5 xc3x85;
b) the distance from the center of mass of the moderately hydrophobic moiety in the P4 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 5.5 xc3x85 and about 8.5 xc3x85; and
c) the distance from the center of mass of the moderately hydrophobic moiety in the P4 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 8 xc3x85 and about 11 xc3x85.
Preferably, any moderately hydrophobic moiety associating with the Pxe2x80x2 binding pocket of ICE does so in such a way that:
a) the distance from the center of mass of the moderately hydrophobic moiety in the Pxe2x80x2 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 11xc3x85 and about 16 xc3x85;
b) the distance from the center of mass of the moderately hydrophobic moiety in the Pxe2x80x2 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 10xc3x85 and about 15 xc3x85; and
c) the distance from the center of mass of the moderately hydrophobic moiety in the Pxe2x80x2 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 8 xc3x85 and about 12 xc3x85.
More preferably, all of the above associative conditions are met in the compounds of this invention.
The practitioner skilled in the art will appreciate that there are a number of means to design the inhibitors of the present invention. These same means may be used to select a candidate compound for screening as an ICE inhibitor. This design or selection may begin with selection of the various moieties which fill binding pockets.
There are a number of ways to select moieties to fill individual binding pockets. These include visual inspection of a physical model or computer model of the active site and manual docking of models of selected moieties into various binding pockets. Modeling software that is well known and available in the art may be used. These include QUANTA [Molecular Simulations, Inc., Burlington, Mass., 1992], SYBYL [Molecular Modeling Software, Tripos Associates, Inc., St. Louis, Mo., 1992], AMBER [S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, and P. Weiner, J. Am. Chem. Soc., vol. 106, pp. 765-784 (1984)], or CHARMM [B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S Swaminathan, and M. Karplus, J. Comp. Chem. vol. 4, pp. 187-217 (1983)]. This modelling step may be followed by energy minimization with standard molecular mechanics forcefields such as CHARMM and AMBER. In addition, there are a number of more specialized computer programs to assist in the process of selecting the binding moieties of this invention. These include:
1. GRID (Goodford, P. J. A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules. J. Med. Chem., 28, pp. 849-857 (1985)). GRID is available from Oxford University, Oxford, UK.
2. MCSS (Miranker, A.; Karplus, M. Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method. Proteins: Structure, Function and Genetics, 11, pp. 29-34 (1991)). MCSS is available from Molecular Simulations, Burlington, Mass.
3. AUTODOCK (Goodsell, D. S.; Olsen, A. J. Automated Docking of Substrates to Proteins by Simmulated Annealing. PROTEINS: Structure, Function and Genetics, 8, pp. 195-202 (1990)). AUTODOCK is available from the Scripps Research Institute, La Jolla, Calif.
4. DOCK (Kuntz, I. D.; Blaney, J. M.; Oatley, S. J.; Langridge, R.; Ferrin, T. E. A Geometric Approach to Macromolecule-Ligand Interactions. J. Mol. Biol., 161, pp. 269-288 (1982)). DOCK is available from the University of California, San Francisco, Calif.
Once suitable binding moieties have been selected, they can be assembled into a single inhibitor. This assembly may be accomplished by connecting the various moieties to a central scaffold. The assembly process may, for example, be done by visual inspection followed by manual model building, again using software such as Quanta or Sybyl. A number of other programs may also be used to help select ways to connect the various moieties. These include:
1. CAVEAT (Bartlett, P. A.; Shea, G. T.; Telfer, S. J.; Waterman, S. CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules. In xe2x80x9cMolecular Recognition in Chemical and Biological Problems,xe2x80x9d Special Pub., Royal Chem. Soc., 78, pp. 182-196 (1989)). CAVEAT is available from the University of California, Berkeley, Calif.
2. 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, Calif.). This area has been recently reviewed by Martin (Martin, Y.C. 3D Database Searching in Drug Design. J. Med. Chem., 35, pp. 2145-2154 (1992)).
3. HOOK (available from Molecular Simulations, Burlington, Mass.).
In addition to the above computer assisted modeling of inhibitor compounds, the inhibitors of this invention may be constructed xe2x80x9cde novoxe2x80x9d using either an empty active site or optionally including some portions of a known inhibitor. Such methods are well known in the art. They include, for example:
1. LUDI (Bohm, H. J. The Computer Program LUDI: A New Method for the De Novo Design of Enzyme Inhibitors. J. Comp. Aid. Molec. Design., 6, 61-78 (1992)). LUDI is available from Biosym Technologies, San Diego, Calif.
2. LEGEND (Nishibata, Y., Itai, A., Tetrahedron, 47, 8985 (1991)). LEGEND is available from Molecular Simultations, Burlington, Mass.
3. LeapFrog (available from Tripos associates, St. Louis, Mo).
A number of techniques commonly used for modeling drugs may be employed (For a review, see: Cohen, N. C.; Blaney, J. M.; Humblet, C.; Gund, P.; Barry, D. C., xe2x80x9cMolecular Modeling Software and Methods for Medicinal Chemistryxe2x80x9d, J. Med. Chem., 33, pp. 883-894 (1990)). There are likewise a number of examples in the chemical literature of techniques that can be applied to specific drug design projects. For a review, see: Navia, M. A. and Murcko, M. A., xe2x80x9cThe Use of Structural Information in Drug Designxe2x80x9d Current Opinions in Structural Biology, 2, pp. 202-210 (1992). Some examples of these specific applications include: Baldwin, J. J. et al., xe2x80x9cThienothiopyran-2-sulfonamides: Novel Topically Active Carbonic Anhydrase Inhibitors for the Treatment of Glaucomaxe2x80x9d, J. Med. Chem., 32, pp. 2510-2513 (1989); Appelt, K. et al., xe2x80x9cDesign of Enzyme Inhibitors Using Iterative Protein Crystallographic Analysisxe2x80x9d, J. Med. Chem., 34, pp. 1925-1934 (1991); and Ealick, S. E. et al., xe2x80x9cApplication of Crystallographic and Modeling Methods in the Design of Purine Nucleotide Phosphorylase Inhibitorsxe2x80x9d Proc. Nat. Acad. Sci. USA, 88, pp. 11540-11544 (1991).
Using the novel combination of steps of the present invention, the skilled artisan can advantageously avoid time consuming and expensive experimentation to determine enzymatic inhibition activity of particular compounds. The method also is useful to facilitate rational design of ICE inhibitors and therapeutic and prophylactic agents against IL-1-mediated diseases. Accordingly, the present invention relates to such inhibitors.
A variety of conventional techniques may be used to carry out each of the above evaluations as well as the evaluations necessary in screening a candidate compound for ICE inhibiting activity. Generally, these techniques involve determining the location and binding proximity of a given moiety, the occupied space of a bound inhibitor, the deformation energy of binding of a given compound and electrostatic interaction energies. Examples of conventional techniques useful in the above evaluations include: quantum mechanics, molecular mechanics, molecular dynamics, Monte Carlo sampling, systematic searches and distance geometry methods (G. R. Marshall, Ann. Ref. Pharmacol. Toxicol., 27, p. 193 (1987)). Specific computer software has been developed for use in carrying out these methods. Examples of programs designed for such uses include: Gaussian 92, revision E.2 (M. J. Frisch, Gaussian, Inc., Pittsburgh, Pa. (copyright)1993); AMBER, version 4.0 (P. A. Kollman, University of California at San Francisco, (copyright)1993); QUANTA/CHARMM [Molecular Simulations, Inc., Burlington, Mass. (copyright)1992]; and Insight II/Discover (Biosysm Technologies Inc., San Diego, Calif. (copyright)1992). These programs may be implemented, for instance, using a Silicon Graphics Indigo 2 workstation or IBM RISC/6000 workstation model 550. Other hardware systems and software packages will be known and of evident applicability to those skilled in the art.
Different classes of active ICE inhibitors, according to this invention, may interact in similar ways with the various binding pockets of the ICE active site. The spatial arrangement of these important groups is often referred to as a pharmacophore. The concept of the pharmacophore has been well described in the literature (D. Mayer, C. B. Naylor, I. Motoc, and G. R. Marshall, J. Comp. Aided Molec. Design vol. 1, pp. 3-16 (1987); A. Hopfinger and B. J. Burke, in Concepts and Applications of Molecular Similarity, M. A. Johnson and G. M. Maggiora, ed., Wiley (1990)).
Different classes of ICE inhibitors of this invention may also use different scaffolds or core structures, but all of these cores will allow the necessary moieties to be placed in the active site such that the specific interactions necessary for binding may be obtained. These compounds are best defined in terms of their ability to match the pharmacophore, i.e., their structural identity relative to the shape and properties of the active site of ICE.
The ICE inhibitors of one embodiment of this invention comprise a first and a second hydrogen bonding moiety, a first and a second moderately hydrophobic moiety, and an electronegative moiety which comprise or are covalently bound to one of the following scaffolds: 
The ICE inhibitors of another embodiment (A) of this invention are those of formula xcex1: 
wherein:
X1 is CH or N;
g is 0 or 1;
each J is independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, and xe2x80x94F, provided that when a first and second J are bound to a C and said first J is xe2x80x94OH, said second J is xe2x80x94H;
m is 0, 1, or 2;
T is xe2x80x94Ar3, xe2x80x94OH, xe2x80x94CF3, xe2x80x94COxe2x80x94CO2H, xe2x80x94CO2H or any bioisosteric replacement for xe2x80x94CO2H;
R1 is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q1, at any nitrogen by R5, or at any atom by xe2x95x90O, xe2x80x94OH, xe2x80x94CO2H, or halogen, and in which any saturated ring may optionally be unsaturated at one or two bonds: 
R20 is selected from the group consisting of: 
xe2x80x83wherein each ring C is independently chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R3 is
xe2x80x94CN,
xe2x80x94CHxe2x95x90CHxe2x80x94R9,
xe2x80x94CHxe2x95x90Nxe2x80x94Oxe2x80x94R9,
xe2x80x94(CH2)1-3xe2x80x94T1xe2x80x94R9,
xe2x80x94CJ2xe2x80x94R9,
xe2x80x94COxe2x80x94R13, or 
each R4 is independently selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94T1xe2x80x94R9, and
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9,
each T1 is independently selected from the group consisting of:
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94SOxe2x80x94,
xe2x80x94SO2xe2x80x94,
xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94SO2xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94SO2xe2x80x94, and
xe2x80x94NR10xe2x80x94SO2xe2x80x94NR10xe2x80x94,
each R5 is independently selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94COxe2x80x94Ar1,
xe2x80x94SO2xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94COxe2x80x94R9,
xe2x80x94COxe2x80x94Oxe2x80x94R9,
xe2x80x94SO2xe2x80x94R9, 
R6 and R7 taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94, or
R7 is xe2x80x94H and R6 is
xe2x80x94H
xe2x80x94Ar1,
xe2x80x94R9, or
xe2x80x94(CH2)1,2,3xe2x80x94T1-R9;
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted by xe2x80x94OH, xe2x80x94F, or xe2x95x90O and optionally substituted with one or two Ar1 groups;
each R10 is independently selected from the group consisting of xe2x80x94H or a C1-6 straight or branched alkyl group;
each R13 is independently selected from the group consisting of xe2x80x94Ar2 and xe2x80x94R4;
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by xe2x95x90O, xe2x80x94OH, perfluoro C1-3 alkyl, or xe2x80x94Q1;
each Ar2 is independently selected from the following group, in which any ring may optionally be substituted by xe2x80x94Q1: 
Ar3 is a cyclic group selected from the set consisting of a phenyl ring, a 5-membered heteroaromatic ring, and a 6-membered heteroaromatic ring, said heteroaromatic rings comprising 1-3 heteroatom groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said cyclic group optionally being singly or multiply substituted with xe2x95x90O, xe2x80x94OH, halogen, perfluoro C1-3 alkyl, or xe2x80x94CO2H;
each Q1 is independently selected from the group consisting of:
xe2x80x94Ar1 
xe2x80x94R9,
xe2x80x94T1xe2x80x94R9, and
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9,
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1;
each X is independently selected from the group consisting of xe2x95x90Nxe2x80x94, and xe2x95x90CHxe2x80x94;
each X2 is independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2; each X3 is independently selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2xe2x80x94;
each X4 is independently selected from the group consisting of xe2x80x94CH2xe2x80x94 and xe2x80x94NHxe2x80x94;
each X5 is independently selected from the group consisting of 
X6 is CH or N, provided that when X6 is N in the R1 group labeled (o) and X5 is CH and X2 is CH2 the ring of the R1 group labeled (o) must be substituted by Q1 or benzofused;
each Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94;
each Z is independently CO or SO2,
each a is independently 0 or 1,
each c is independently 1 or 2,
each d is independently 0, 1, or 2, and
each e is independently 0, 1, 2, or 3.
The ICE inhibitors of another embodiment (B) of this invention are those of formula xcex1: 
wherein:
X1 is xe2x80x94CH;
g is 0 or 1;
each J is independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, and xe2x80x94F, provided that when a first and second J are bound to a C and said first J is xe2x80x94OH, said second J is xe2x80x94H;
m is 0, 1, or 2;
T is xe2x80x94OH, xe2x80x94COxe2x80x94CO2H, xe2x80x94CO2H or any bioisosteric replacement for xe2x80x94CO2H;
R1 is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q1, at any nitrogen by R5, or at any atom by xe2x95x90O, xe2x80x94OH, xe2x80x94CO2H, or halogen, any saturated ring may optionally be unsaturated at one or two bonds; and wherein R1 (e) and R1 (y) are optionally benzofused; 
R20 is selected from the group consisting of: 
xe2x80x83wherein each ring C is independently chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R3 is
xe2x80x94CN,
xe2x80x94CHxe2x95x90CHxe2x80x94R9,
xe2x80x94CHxe2x95x90Nxe2x80x94Oxe2x80x94R9,
xe2x80x94(CH2)1-3xe2x80x94T1xe2x80x94R9,
xe2x80x94CJ2xe2x80x94R9,
xe2x80x94COxe2x80x94R13, or 
each R4 is independently selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94T1xe2x80x94R9, and
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9,
each T1 is independently selected from the group consisting of:
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94SOxe2x80x94,
xe2x80x94SO2xe2x80x94,
xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94SO2xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94SO2xe2x80x94; and
xe2x80x94NR10xe2x80x94SO2xe2x80x94NR10xe2x80x94,
each R5 is independently selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94COxe2x80x94Ar1,
xe2x80x94SO2xe2x80x94Ar1,
xe2x80x94COxe2x80x94NH2,
xe2x80x94SO2xe2x80x94NH2,
xe2x80x94R9,
xe2x80x94COxe2x80x94R9,
xe2x80x94COxe2x80x94Oxe2x80x94R9,
xe2x80x94SO2xe2x80x94R9, 
R6 and R7 taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94; or
R7 is xe2x80x94H and R6 is:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9, or
an xcex1-amino acid side chain residue;
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted by xe2x80x94OH, xe2x80x94F, or xe2x95x90O and optionally substituted with one or two Ar1 groups;
each R10 is independently selected from the group consisting of xe2x80x94H or a C1-6 straight or branched alkyl group;
each R13 is independently selected from the group consisting of xe2x80x94Ar2, xe2x80x94R4 and 
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
each Ar2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by xe2x80x94Q1 and xe2x80x94Q2: 
each Q1 is independently selected from the group consisting of
xe2x80x94Ar1,
xe2x80x94Oxe2x80x94Ar1
xe2x80x94R9,
xe2x80x94T1xe2x80x94R9, and
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9;
each Q2 is independently selected from the group consisting of xe2x80x94OH, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, and 
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1;
each X is independently selected from the group consisting of xe2x95x90Nxe2x80x94, and xe2x95x90CHxe2x80x94;
each X2 is independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2xe2x80x94;
each X3 is independently selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2xe2x80x94;
each X4 is independently selected from the group consisting of xe2x80x94CH2xe2x80x94 and xe2x80x94NHxe2x80x94;
each X5 is independently selected from the group consisting of 
X6 is CH or N, provided that when X6 is N in the R1, group labeled (o) and X5 is CH and X2 is CH2 the ring of the R1 group labeled (o) must be substituted by Q1 or benzofused;
each Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94, and xe2x80x94NH;
each Z is independently CO or SO2,
each a is independently 0 or 1,
each c is independently 1 or 2,
each d is independently 0, 1, or 2, and
each e is independently 0, 1, 2, or 3,
provided that when
R1 is (f),
R6 is an xcex1-amino acid side chain residue, and
R7 is xe2x80x94H,
then (aa1) and (aa2) must be substituted with Q1;
also provided that when
R1 is (o),
g is 0,
J is xe2x80x94H,
m is 1,
R6 is an xcex1-amino acid side chain residue,
R7 is xe2x80x94H,
X2 is xe2x80x94CH2xe2x80x94, 
and
R3 is 
or xe2x80x94COxe2x80x94R13, when
R13 is:
xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Sxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Sxe2x80x94Ar1, or
xe2x80x94R4 when xe2x80x94R4 is xe2x80x94H;
then the ring of the R1 (o) group must be substituted with Q1 or benzofused; and
provided that when
R1 is (w),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H or xe2x80x94COxe2x80x94NHxe2x80x94OH,
X2 is O,
R5 is benzyloxycarbonyl, and
ring C is benzo,
then R3 cannot be xe2x80x94COxe2x80x94R13 when:
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1 and
Ar1 is 1-phenyl-3-chloro- or 3-trifluoromethyl-pyrazole-5-yl;
or when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1 and
Ar1 is 2,6-dichlorophenyl.
Preferred forms of the R1 group (a) for embodiments A and B are: 
Preferred forms of the R1 group (b) are: 
Preferred forms of the R1 group (c) are: 
provided that when R1 is (cl),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H,
X is N,
R5 is benzyloxycarbonyl, and
R6 is xe2x80x94H,
then R3 cannot be xe2x80x94COxe2x80x94R13 when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1 and
Ar1 is a chloro-substituted 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, or when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1 and
Ar1 is 2,6-dichlorophenyl,
and when the 2-position of the scaffold ring is substituted with para-fluoro-phenyl;
Preferred forms of the R1 group (d) are: 
Preferred forms of the R1 group (e) are: 
which is optionally benzofused; 
provided that when R1 is (e4),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H,
R5 is benzyloxycarbonyl, and
c is 1,
then R3 cannot be xe2x80x94COxe2x80x94R13 when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1 and
Ar1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, wherein the phenyl is optionally substituted with a chlorine atom; or when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1 and
Ar1 is 2,6-dichlorophenyl,
and when the 2-position of the scaffold ring is substituted with para-fluoro-phenyl; and
also provided that when
R1 is (e7),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H or xe2x80x94COxe2x80x94NHxe2x80x94OH,
R5 is a protective group for the N atom of an amino acid side chain residue, and
each c is 1,
then R3 cannot be xe2x80x94COxe2x80x94R13 when R13 is:
xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Sxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1, or
xe2x80x94CH2xe2x80x94Sxe2x80x94Ar1.
Preferred forms of the R1 group (g) are: 
Preferred forms of the R1 group (h) are: 
Preferred forms of the R1 group (i) are: 
Preferred forms of the R1 group (j) are: 
Preferred forms of the R1 group (k) are: 
Preferred forms of the R1 group (l) are: 
Preferred forms of the R1 group (m) are: 
Preferred forms of the R1 group (n) are: 
Preferred forms of the R1 group (o) are: 
A preferred form of the R1 group (o) of embodiment B is: 
wherein X2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94NHxe2x80x94.
For embodiments A and B, preferred forms of the R1 group (p) are: 
Preferred forms of the R1 group (q) are: 
Preferred forms of the R1 group (r) are: 
Preferred forms of the R1 group (s) are: 
Preferred forms of the R1 group (t) are: 
Preferred forms of the R1 group (v) are: 
A preferred form of the R1 group (w) of embodiment B is: 
wherein X2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NHxe2x80x94.
The preferred compounds of embodiments A and B of this invention are those which employ formula xcex1, wherein:
X1 is CH;
g is O;
J is xe2x80x94H;
m is 0 or 1 and T is xe2x80x94Ar3, xe2x80x94COxe2x80x94CO2H, xe2x80x94CO2H or any bioisosteric replacement for xe2x80x94CO2H, or
m is 1 or 2 and T is xe2x80x94OH, xe2x80x94CF3, or xe2x80x94CO2H;
more preferably m is 1 and T is xe2x80x94CO2H;
R1 is 
R20 is 
xe2x80x83wherein ring C is benzo;
R3 is
xe2x80x94COxe2x80x94R13, or 
most preferably R3 is any one of 1), 2) or 3) as follows: 1) xe2x80x94COxe2x80x94Ar2, 2) xe2x80x94COxe2x80x94R9 where R9 is C3-6 alkyl substituted with two Ar1 groups or one Ar1 group itself substituted with an Ar1 group, xe2x80x94C1-2xe2x80x94Ar1, xe2x80x94Cl, xe2x80x94CH3, or xe2x80x94CF3, or 3)xe2x80x94(CH2)1,2xe2x80x94T1xe2x80x94R9 where T1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and R9 is C1-2 alkyl substituted with two Ar1 groups or one Ar1 group itself substituted with an Ar1 group, C1-2xe2x80x94Ar1, xe2x80x94Cl, xe2x80x94CH3, or xe2x80x94CF3;
R4 is xe2x80x94H or xe2x80x94R9;
T1 is
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94COxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94, or
xe2x80x94SO2xe2x80x94;
when R1 is (a), (b), (k), or (m), R5 is preferably xe2x80x94Ar1 or C1-4xe2x80x94Ar1;
when R1 is (c), (e), (f), (o), or (r), R5 is preferably xe2x80x94SO2xe2x80x94Ar1, xe2x80x94SO2xe2x80x94R9, or xe2x80x94COxe2x80x94C1-4xe2x80x94Ar1;
R7 is xe2x80x94H and R6 is C1-4xe2x80x94Ar1;
R10 is xe2x80x94H or a C1-3 straight or branched alkyl group;
R13 is xe2x80x94Ar2;
Ar1 is phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, benzothienyl, benzoxazolyl, 2-indanyl, or indolyl;
Ar2 is preferably substituted with xe2x80x94Ar1, or xe2x80x94C1-4xe2x80x94Ar1;
Ar3 is phenyl, thiophene, thiazole, pyridine, or oxazole; and
Q1 is xe2x80x94R9 or xe2x80x94(CH2)1,2xe2x80x94T1xe2x80x94(CH2)1-3xe2x80x94Ar1 where T1 is xe2x80x94Oxe2x80x94or xe2x80x94Sxe2x80x94.
In connection with this continuation-in-part, we now prefer the compounds of embodiment B of this invention which employ formula xcex1, wherein:
X1 is xe2x80x94CH;
g is O
J is xe2x80x94H;
m is 0 or 1 and T is xe2x80x94COxe2x80x94CO2H, or any bioisosteric replacement for xe2x80x94CO2H; or
m is 1 and T is xe2x80x94CO2H;
R1 is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q1, at any nitrogen by R5, or at any atom by xe2x95x90O, xe2x80x94OH, xe2x80x94CO2H, or halogen, and wherein (e) is optionally benzofused: 
R20 is 
xe2x80x83and c is 1;
ring C is benzo optionally substituted with xe2x80x94C1-3 alkyl, xe2x80x94Oxe2x80x94C1-3 alkyl, xe2x80x94Cl, xe2x80x94F or xe2x80x94CF3;
R3 is:
xe2x80x94COxe2x80x94R13, or 
more preferably R3 is any one of 1), 2) or 3) as follows: 1) xe2x80x94COxe2x80x94Ar2; 2) xe2x80x94COxe2x80x94R9 where R9 is C1-5 alkyl substituted with an Ar1; or 3) xe2x80x94CH2xe2x80x94T1xe2x80x94R9 where T1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and R9 is C1-2 alkyl substituted with one Ar1 group;
R4 is xe2x80x94H or xe2x80x94R9;
T1 is:
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94COxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94, or
xe2x80x94SO2xe2x80x94;
when R1 is (a) or (b), R5 is preferably xe2x80x94H, and when R1 is (c), (e), (f), (o), (r), (w), (x) or (y), R5 is preferably:
xe2x80x94COxe2x80x94Ar1 
xe2x80x94SO2xe2x80x94Ar1,
xe2x80x94COxe2x80x94NH2,
xe2x80x94COxe2x80x94NHxe2x80x94Ar1 
xe2x80x94COxe2x80x94R9,
xe2x80x94COxe2x80x94Oxe2x80x94R9,
xe2x80x94SO2xe2x80x94R9, or
xe2x80x94COxe2x80x94NHxe2x80x94R9,
R7 is xe2x80x94H and R6 is
xe2x80x94H,
xe2x80x94R9 or
xe2x80x94Ar1;
R9 is C1-6 straight or branched alkyl group optionally substituted with xe2x95x90O and optionally substituted with xe2x80x94Ar1;
R10 is xe2x80x94H or a C1-3 straight or branched alkyl group;
R13 is:
xe2x80x94H,
xe2x80x94R9,
xe2x80x94Ar2, or
xe2x80x94CH2xe2x80x94T1xe2x80x94R9,
more preferably where xe2x80x94Ar2 is (hh) and where (hh) is optionally substituted singly or multiply with xe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94NHxe2x80x94C1-6 alkyl, xe2x80x94Nxe2x80x94(C1-6 alkyl)2, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Cl, xe2x80x94F, xe2x80x94CF3, or 
Ar1 is phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, benzothienyl, benzoxazolyl, 2-indanyl, or indolyl substituted with xe2x80x94Oxe2x80x94C1-3 alkyl, xe2x80x94NHxe2x80x94C1-3 alkyl, xe2x80x94Nxe2x80x94(C1-3 alkyl)2, xe2x80x94Cl, xe2x80x94F, xe2x80x94CF3, xe2x80x94C1-3 alkyl, or 
preferably where Ar2 is: 
each X is independently selected from the group consisting of xe2x95x90Nxe2x80x94, and xe2x95x90CHxe2x80x94;
each X2 is independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2xe2x80x94;
each X5 is independently selected from the group consisting of 
X6 is 
and
Z is Cxe2x95x90O;
provided that when
R1 is (f),
R6 is an xcex1-amino acid side chain residue, and
R7 is xe2x80x94H,
then (aa1) and (aa2) must be substituted with Q1;
also provided that when
R1 is (o),
g is 0,
J is xe2x80x94H,
m is 1,
R6 is an xcex1-amino acid side chain residue,
R7 is xe2x80x94H,
X2 is xe2x80x94CH2xe2x80x94,
X5 is 
X6 is 
and
R3 is 
xe2x80x83or
xe2x80x94COxe2x80x94R13, when
R13 is:
xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Sxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Sxe2x80x94Ar1, or
xe2x80x94R4 when xe2x80x94R4 is xe2x80x94H;
then the ring of the R1 (o) group must be substituted with Q1 or benzofused; and
provided that when
R1 is (w),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H,
X2 is O
R5 is benzyloxycarbonyl, and
ring C is benzo,
then R3 cannot be xe2x80x94COxe2x80x94R13 when:
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1 and
Ar1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, wherein the phenyl is optionally substituted with a chlorine atom;
or when R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1, wherein Ar1 is 2,6-dichlorophenyl.
A preferred form of R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94R9, wherein R9 is a C1-6 straight or branched alkyl group optionally substituted with xe2x95x90O and optionally substituted with Ar1;
another preferred form of R13 is CH2xe2x80x94Sxe2x80x94R9, wherein R9 is a C1-6 straight or branched alkyl group optionally substituted with Ar1;
another preferred form of R13 is CH2xe2x80x94Oxe2x80x94R9 wherein R9 is a C1-6 straight or branched alkyl group optionally substituted with Ar1;
another preferred form of R13 is H.
A more preferred form of the R1 group (a) is: 
optionally substituted with Q1, wherein
X R5 is xe2x80x94H;
R7 is xe2x80x94H; and
Z is Cxe2x95x90O;
a more preferred form of the R1 group (b) is: 
optionally substituted with Q1, wherein
R5 is xe2x80x94H;
R7 is xe2x80x94H; and
Z is Cxe2x95x90O;
more preferred forms of the R1 group (c) are: 
provided that when R1 is (cl),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H,
X is N,
R5 is benzyloxycarbonyl, and
R6 is xe2x80x94H,
then R3 cannot be xe2x80x94COxe2x80x94R13 when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1 and
Ar1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl wherein the phenyl is optionally substituted with a chlorine atom; or when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1, wherein
Ar1 is 2,6-dichlorophenyl, and wherein the 2-position of the scaffold ring is substituted with para-fluoro-phenyl;
more preferred forms of the R1 group (e) are: 
wherein c is 2; and 
xe2x80x83which is optionally benzofused,
wherein c is 1 or 2;
provided that when R1 is (e4),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H,
R5 is benzyloxycarbonyl, and
c is 1,
then R3 cannot be xe2x80x94COxe2x80x94R13 when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1 and
Ar1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl wherein the phenyl is optionally substituted with a chlorine atom; or when
R13 is xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1, wherein
Ar1 is 2,6-dichlorophenyl, and wherein the 2-position of the scaffold ring is substituted with para-fluoro-phenyl; and
also provided that when
R1 is (e7),
g is 0,
J is xe2x80x94H,
m is 1,
T is xe2x80x94CO2H, xe2x80x94COxe2x80x94NHxe2x80x94OH, or a bioisosteric replacement for xe2x80x94CO2H,
R5 is a protective group for the N atom of an xcex1-amino acid side chain residue, and
each c is 1,
then R3 cannot be xe2x80x94COxe2x80x94R13 when R13 is:
xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Sxe2x80x94COxe2x80x94Ar1,
xe2x80x94CH2xe2x80x94Oxe2x80x94Ar1, or
xe2x80x94CH2xe2x80x94Sxe2x80x94Ar1.
a more preferred form of the R1 group (f) is 
a more preferred form of the R1 group (g) is: 
R20 is (aa1) optionally substituted singly or multiply with Q1; and
Z is Cxe2x95x90O;
a more preferred form of the R1 group (h) is: 
R20 is (aa1) optionally substituted singly or multiply with Q1; and
Z is Cxe2x95x90O;
more preferred forms of the R1 group (o) are: 
wherein d is 1 or 2; and 
more preferred forms of the R1 group (r) are: 
optionally substituted with Q1;
a more preferred form of the R1 group (w) is: 
X2 is:
xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94Oxe2x80x94, or
xe2x80x94SO2xe2x80x94;
optionally substituted with R5 or Q1 at X2 when X2 is xe2x80x94Nxe2x80x94; and
ring C is benzo substituted with xe2x80x94C1-3 alkyl, xe2x80x94Oxe2x80x94C1-3 alkyl, xe2x80x94Cl, xe2x80x94F or xe2x80x94CF3. 
preferred compounds of this invention include but are not limited to: 
A preferred compound of embodiment B of this invention employs formula xcex1, wherein the R1 is: 
Preferred compounds of this embodiment include but are not limited to: 
When R1 is: 
preferred compounds of this invention include but are not limited to: 
A preferred compound of embodiment B of this invention employs formula xcex1, wherein:
R1 is: 
xe2x80x83and c is 2;
m is 1;
T is xe2x80x94CO2H; and
R3 is xe2x80x94COxe2x80x94R13.
Preferred compounds of this embodiment include but are not limited to: 
When R1 is: 
preferred compounds of this invention include but are not limited to: 
When R1 is: 
preferred compounds of this invention include but are not limited to: 
When R1 is: 
preferred compounds of this invention include but are not limited to: 
A preferred compound of embodiment B of this invention employs formula xcex1, wherein:
R1 is: 
X2 is xe2x80x94NHxe2x80x94;
m is 1;
T is xe2x80x94CO2H;
R3 is xe2x80x94COxe2x80x94R13.
Preferred compounds of this embodiment include but are not limited to: 
When R1 is: 
optionally substituted with Q1;
preferred compounds of embodiment B of this invention include but are not limited to: 
When R1 is: 
preferred compounds of this invention include but are not limited to: 
The ICE inhibitors of another embodiment (C) of this invention are represented by the formula "sgr": 
wherein the ring is optionally substituted with one or more R groups, preferably 0, 1 or 2; and wherein:
R1 is R5xe2x80x94(A)pxe2x80x94;
R5 is selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94COxe2x80x94Ar1,
xe2x80x94SO2xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94COxe2x80x94R9,
xe2x80x94COxe2x80x94Oxe2x80x94R9,
xe2x80x94SO2xe2x80x94R9, 
each A is independently selected from the group consisiting of any xcex1-amino acid;
p is 0, 1, 2, 3 or 4;
Y is:
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94 or
xe2x80x94NH;
R is:
xe2x80x94H,
xe2x80x94Oxe2x80x94C1-6 alkyl,
xe2x80x94NH(C1-6 alkyl),
xe2x80x94N (C1-6 alkyl)2,
xe2x80x94Sxe2x80x94C1-6 alkyl,
xe2x80x94C1-6 alkyl, or
xe2x80x94Q2;
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted by xe2x80x94OH, xe2x80x94F, or xe2x95x90O and optionally substituted with one or two Ar1 groups;
each R10 is independently selected from the group consisting of xe2x80x94H or a C1-6 straight or branched alkyl group;
each T1 is independently selected from the group consisting of:
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94SOxe2x80x94,
xe2x80x94SO2xe2x80x94,
xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94SO2xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94SO2xe2x80x94, and
xe2x80x94NR10xe2x80x94SO2xe2x80x94NR10xe2x80x94,
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by: xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
each Q1 is independently selected from the group consisting of:
xe2x80x94Ar1 
xe2x80x94R9,
xe2x80x94T1xe2x80x94R9, and
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9;
each Q2 is independently selected from the group consisting of xe2x80x94OH, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, and 
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1.
Preferred compounds of embodiment C of this invention include but are not limited to: 
Preferred compounds of embodiment C of this invention are also those in which each A is independently selected from the group consisting of the xcex1-amino acids:
alanine,
histidine,
lysine,
phenylalanine,
proline,
tyrosine,
valine,
leucine,
isoleucine,
glutamine,
methionine,
homoproline,
3-(2-thienyl) alanine, and
3-(3-thienyl) alanine.
The ICE inhibitors of another embodiment (D) of this invention are represented by the formula xcfx80: 
wherein:
R1 is R5xe2x80x94(A)pxe2x80x94;
each T1 is independently selected from the group consisting of:
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94SOxe2x80x94,
xe2x80x94SO2xe2x80x94,
xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94SO2xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94SO2xe2x80x94, and
xe2x80x94NR10xe2x80x94SO2xe2x80x94NR10xe2x80x94;
R5 is selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94COxe2x80x94Ar1,
xe2x80x94SO2xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94COxe2x80x94R9,
xe2x80x94COxe2x80x94Oxe2x80x94R9,
xe2x80x94SO2xe2x80x94R9, 
each A is independently selected from the group consisiting of any xcex1-amino acid;
p is 0, 1, 2, 3 or 4;
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted by xe2x80x94OH, xe2x80x94F, or xe2x95x90O and optionally substituted with an Ar1 group;
each R10 is independently selected from the group consisting of xe2x80x94H or a C1-6 straight or branched alkyl group;
Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CH, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, or 
Preferred compounds of embodiment D of this invention are those in which R9 is a C1-4 straight or branched alkyl substituted with Ar1 when Ar1 is phenyl.
Preferred compounds of embodiment D of this invention include but are not limited to: 
Preferred compounds of embodiment D of this. invention are also those in which A is independently selected from the group consisting of the xcex1-amino acids:
alanine,
histidine,
lysine,
phenylalanine,
proline,
tyrosine,
valine,
leucine,
isoleucine,
glutamine,
methionine,
homoproline,
3-(2-thienyl) alanine, and
3-(3-thienyl) alanine.
The ICE inhibitors of another embodiment (E) of this invention are represented by formula xcex3: 
wherein:
m is 0, 1, or 2;
T is xe2x80x94CO2H, or any bioisosteric replacement for xe2x80x94CO2H,
R3 is
xe2x80x94CN,
xe2x80x94COR13, or 
R5 is selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94COxe2x80x94Ar1,
xe2x80x94SO2xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94COxe2x80x94R9,
xe2x80x94COxe2x80x94Oxe2x80x94R9,
xe2x80x94SO2xe2x80x94R9, 
each A is independently selected from the group consisting of any xcex1-amino acid;
p is 2 or 3;
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted by xe2x80x94OH, xe2x80x94F, or xe2x95x90O and optionally substituted with one Ar1 group;
each T1 is independently selected from the group consisting of:
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94SOxe2x80x94,
xe2x80x94SO2xe2x80x94,
xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94NR10xe2x80x94COxe2x80x94NR10xe2x80x94,
xe2x80x94SO2xe2x80x94NR10xe2x80x94,
xe2x80x94NR10xe2x80x94SO2xe2x80x94, and
xe2x80x94NR10xe2x80x94SO2xe2x80x94NR10xe2x80x94;
each R10 is independently selected from the group consisting of xe2x80x94H or a xe2x80x94C1-6 straight or branched alkyl group;
each R13 is independently selected from the group consisting of H, R9, Ar2, and CH2T1R9;
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
xe2x80x83and
each Ar2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by xe2x80x94Q1 and xe2x80x94Q2: 
each Q1 is independently selected from the group consisting of:
xe2x80x94Ar
xe2x80x94Oxe2x80x94Ar1 
xe2x80x94R9,
xe2x80x94T1xe2x80x94R9, and
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9;
each Q2 is independently selected from the group consisting of xe2x80x94OH, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, and 
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1.
Preferred compounds of embodiment E of this invention include but are not limited to: 
Preferred compounds of embodiment E of this invention are also those in which A is independently selected from the group consisting the xcex1-amino acids:
alanine,
histidine,
lysine,
phenylalanine,
proline,
tyrosine,
valine,
leucine,
isoleucine,
glutamine,
methionine,
homoproline,
3-(2-thienyl) alanine, and
3-(3-thienyl) alanine.
The ICE inhibitors of another embodiment (F) of this invention are represented by formula xcex4: 
wherein:
R1 is R5xe2x80x94(A)pxe2x80x94;
R5 is selected from the group consisting of:
xe2x80x94H,
xe2x80x94Ar1,
xe2x80x94COxe2x80x94Ar1,
xe2x80x94SO2xe2x80x94Ar1,
xe2x80x94R9,
xe2x80x94COxe2x80x94R9,
xe2x80x94COxe2x80x94Oxe2x80x94R9,
xe2x80x94SO2xe2x80x94R9, 
each A is independently selected from the group consisting of any xcex1-amino acid;
p is 0, 1, 2, 3 or 4;
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted by xe2x80x94OH, xe2x80x94F, or xe2x95x90O and optionally substituted with one Ar1 group;
each R10 is independently selected from the group consisting of xe2x80x94H or a C1-6 straight or branched alkyl group;
each T1 is independently selected from the group consisting of:
xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94Oxe2x80x94,
xe2x80x94Sxe2x80x94,
xe2x80x94SOxe2x80x94,
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
xe2x80x83and
each Ar2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by xe2x80x94Q1 and xe2x80x94Q2: 
each Q1 is independently selected from the group consisting of:
xe2x80x94Ar1 
xe2x80x94Oxe2x80x94Ar1 
xe2x80x94R9,
xe2x80x94T1xe2x80x94R9, and
xe2x80x94(CH2)1,2,3xe2x80x94T1xe2x80x94R9;
each Q2 is independently selected from the group consisting of xe2x80x94OH, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, and 
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1;
each X is independently selected from the group consisting of xe2x95x90Nxe2x80x94, and xe2x95x90CHxe2x80x94; and
each Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NH.
Preferred compounds of emvodiment F of this include but are not limited to: 
Preferred compounds of embodiment F of this invention are also those in which A is independently selected from the group consisting the xcex1-amino acids:
alanine,
histidine,
lysine,
phenylalanine,
proline,
tyrosine,
valine,
leucine,
isoleucine,
glutamine,
methionine,
homoproline,
3-(2-thienyl) alanine, and
3-(3-thienyl) alanine.
The compounds of this invention having a molecular weight of less than or equal to about 700 Daltons, and more preferably between about 400 and 600 Daltons, are preferred. These preferred compounds may be readily absorbed by the bloodstream of patients upon oral administration. This oral availability makes such compounds excellent agents for orally-administered treatment and prevention regimens against IL-1 mediated diseases.
The ICE inhibitors of this invention may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.
The compounds of this invention are among the most readily synthesized ICE inhibitors known. Previously described ICE inhibitors often contain four or more chiral centers and numerous peptide linkages. The relative ease with which the compounds of this invention can be synthesized represents an enormous advantage in the large scale production of these compounds.
It should be understood that the compounds of this invention may exist in various equilibrium forms, depending on conditions including choice of solvent, pH, and others known to the practitioner skilled in the art. All such forms of these compounds are expressly included in the present invention. In particular, many of the compounds of this invention, especially those which contain aldehyde or ketone groups in R3 and carboxylic acid groups in T, may take hemi-ketal (or hemi-acetal) or hydrated forms, as depicted below: 
Depending on the choice of solvent and other conditions known to the practitioner skilled in the art, compounds of this invention may also take acyloxy ketal, acyloxy acetal, ketal or acetal form: 
In addition, it should be understood that the equilibrium forms of the compounds of this invention may include tautomeric forms. All such forms of these compounds are expressly included in the present invention.
It should be understood that the compounds of this invention may be modified by appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. In addition, the compounds may be altered to pro-drug form such that the desired compound is created in the body of the patient as the result of the action of metabolic or other biochemical processes on the pro-drug. Some examples of pro-drug forms include ketal, acetal, oxime, and hydrazone forms of compounds which contain ketone or aldehyde groups, especially where they occur in the R3 group of the compounds of this invention.
The compounds of this invention are excellent ligands for ICE. Accordingly, these compounds are capable of targeting and inhibiting events in IL-1 mediated diseases, such as the conversion of precursor IL-1xcex2 to mature IL-1xcex2 and, thus, the ultimate activity of that protein in inflammatory diseases, autoimmune diseases and neurodegenerative diseases. For example, the compounds of this invention inhibit the conversion of precursor IL-1xcex2 to mature IL-1xcex2 by inhibiting ICE. Because ICE is essential for the production of mature IL-1, inhibition of that enzyme effectively blocks initiation of IL-1 mediated physiological effects and symptoms, such as inflammation, by inhibiting the production of mature IL-1. Thus, by inhibiting IL-1xcex2 precursor activity, the compounds of this invention effectively function as IL-1 inhibitors.
The compounds of this invention may be employed in a conventional manner for the treatment of diseases which are mediated by IL-1. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For example, a compound of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from an IL-1 mediated disease in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of that disease.
Alternatively, the compounds of this invention may be used in compositions and methods for treating or protecting individuals against IL-1 mediated diseases over extended periods of time. The compounds may be employed in such compositions either alone or together with other compounds of this invention in a manner consistent with the conventional utilization of ICE inhibitors in pharmaceutical compositions. For example, a compound of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period time against IL-1 mediated diseases.
The compounds of this invention may also be co-administered with other ICE inhibitors to increase the effect of therapy or prophylaxis against various IL-1-mediated diseases.
In addition, the compounds of this invention may be used in combination either conventional anti-inflammatory agents or with matrix metalloprotease inhibitors, lipoxygenase inhibitors and antagonists of cytokines other than IL-1xcex2.
The compounds of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) or with prostaglandins, to prevent or combat IL-1-mediated disease symptoms such as inflammation.
When the compounds of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of an ICE inhibitor of this invention and another therapeutic or prophylactic agent.
Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be. employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Hely or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The IL-1 mediated diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, inflammatory diseases, autoimmune diseases and neurodegenerative diseases.
Inflammatory diseases which may be treated or prevented include, for example, septic shock, septicemia, and adult respiratory distress syndrome. Target autoimmune diseases include, for example, rheumatoid, arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves"" disease, autoimmune gastritis, insulin-dependent diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis and multiple sclerosis. And target neurodegenerative diseases include, for example, amyotrophic lateral sclerosis, Alzheimer""s disease, Parkinson""s disease, and primary lateral sclerosis. The ICE inhibitors of this invention may also be used to promote wound healing. And the ICE inhibitors of this invention may be used to treat infectious diseases.
Although this invention focuses on the use of the compounds disclosed herein for preventing and treating IL-1-mediated diseases, the compounds of this invention can also be used as inhibitory agents for other cysteine proteases.
The compounds of this invention are also useful as commercial reagents which effectively bind to ICE or other cysteine proteases. As commercial reagents, the compounds of this invention, and their derivatives, may be used to block proteolysis of a target peptide or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. These and other uses which characterize commercial cystine protease inhibitors will be evident to those of ordinary skill in the art.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.